Methods of using 3-(4-amino-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione for the treatment and management of myelodysplastic syndromes

Abstract

Methods of treating, preventing and/or managing myclodysplastic syndromes are disclosed. Specific methods encompass the administration of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, alone or in combination with a second active ingredient, and/or the transplantation of blood or cells. Specific second active ingredients are capable of affecting or blood cell production. Pharmaceutical compositions, single unit dosage forms, and kits suitable for use in methods of the invention are also disclosed.

1. A method of treating a myelodysplastic syndrome, which comprises administering to a patient in need thereof about 5 to about 50 mg per day of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 
     
     
       2. The method of  claim 1 , wherein the compound is a pharmaceutically acceptable salt. 
     
     
       3. The method of  claim 1 , wherein the compound is a pharmaceutically acceptable solvate. 
     
     
       4. The method of  claim 1 , wherein the compound is a pharmaceutically acceptable stereoisomer. 
     
     
       5. The method of  claim 4 , wherein the stereoisomer is an enantiomerically pure R isomer. 
     
     
       6. The method of  claim 4 , wherein the stereoisomer is an enantiomerically pure S isomer. 
     
     
       7. The method of  claim 1 , which further comprises administering a therapeutically effective amount of a second active agent. 
     
     
       8. The method of  claim 7 , wherein the second active agent is capable of improving blood cell production. 
     
     
       9. The method of  claim 7 , wherein the second active agent is a cytokine, hematopoietic growth factor, an anti-cancer agent, an antibiotic, a proteasome inhibitor, or an immunosuppressive agent. 
     
     
       10. The method of  claim 9 , wherein the second active agent is etanercept, imatinib, anti-TNF-α antibodies, infliximab, G-CSF, GM-CSF, EPO, topotecan, pentoxifylline, ciprofloxacin, irinotecan, vinblastine, dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine, isotretinoin, 13-cis-retinoic acid, arsenic trioxide or a pharmacologically active mutant or derivative thereof. 
     
     
       11. The method of  claim 1 , wherein the myelodysplastic syndrome is refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or chronic myelomonocytic leukemia. 
     
     
       12. The method of  claim 1 , wherein the compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is administered before, during or after transplanting umbilical cord blood, placental blood, peripheral blood stem cell, hematopoietic stem cell preparation or bone marrow in the patient. 
     
     
       13. The method of  claim 10 , wherein the second active agent is dexamethasone. 
     
     
       14. The method of  claim 1 , wherein the patient is not previously treated for a myelodysplastic syndrome. 
     
     
       15. The method of  claim 1 , wherein the patient has been previously treated for a myelodysplastic syndrome. 
     
     
       16. The method of  claim 1 , wherein the compound is administered orally. 
     
     
       17. The method of  claim 16 , wherein the compound is administered in the form of a capsule or tablet. 
     
     
       18. The method of  claim 1 , wherein the compound is administered cyclically. 
     
     
       19. The method of  claim 18 , wherein the compound is administered once or twice every day for sixteen or twenty-four weeks. 
     
     
       20. The method of  claim 18 , wherein one cycle comprises the administration of the compound and at least one, two, or three weeks of rest. 
     
     
       21. The method of  claim 18 , wherein the number of cycle is from one to twelve cycles. 
     
     
       22. The method of  claim 18 , wherein 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is administered in an amount of from about 5 to about 25 mg per day for 21 days every 28 days for sixteen or twenty-four weeks. 
     
     
       23. The method of  claim 3  wherein said solvate is a hydrate. 
     
     
       24. The method of  claim 1 , wherein the compound is administered in an amount of from about 5 mg per day to about 25 mg per day. 
     
     
       25. The method of  claim 1 , wherein the compound is administered in an amount of 10 mg per day. 
     
     
       26. The method of  claim 1 , wherein the compound is administered in an amount of 15 mg per day. 
     
     
       27. The method of  claim 1 , wherein the compound is administered in an amount of 25 mg per day. 
     
     
       28. The method of  claim 1 , wherein the compound is administered in an amount of from about 25 mg every other day to about 50 mg every other day. 
     
     
       29. The method of  claim 1 , wherein the compound is administered in a cycle of about 16 weeks and about once or twice every day. 
     
     
       30. The method of  claim 29 , wherein said cycle comprises at least one (1), two (2), or three (3) weeks of rest. 
     
     
       31. The method of  claim 1 , wherein the compound is administered in an amount of 10 mg per day or 15 mg per day for 21 days out of a block of 28 days. 
     
     
       32. The method of  claim 1 , wherein the compound is administered orally in an amount of 5 mg as a capsule per day. 
     
     
       33. The method of  claim 1 , wherein the compound is administered orally in an amount of 10 mg as a capsule per day. 
     
     
       34. The method of  claim 1 , wherein the compound is 3-(4-amino- 1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione, having the formula: 
       
         
           
           
               
               
           
         
       
       as a free base.